14-50743529-A-G

Variant names:

• chr14-50743529-A-G
• rs61741547
• NM_020921.4:c.5188T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4 BP6 BP7 BS1 BS2

The NM_020921.4(NIN):​c.5188T>C​(p.Leu1730Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,606,684 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0069 (22 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (14 hom.)
• Consequence: NIN NM_020921.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001358
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.528
• Publications: 2 publications found

Genes affected

NIN (HGNC:14906): (ninein) This gene encodes one of the proteins important for centrosomal function. This protein is important for positioning and anchoring the microtubules minus-ends in epithelial cells. Localization of this protein to the centrosome requires three leucine zippers in the central coiled-coil domain. Multiple alternatively spliced transcript variants that encode different isoforms have been reported. [provided by RefSeq, Jul 2008]

NIN Gene-Disease associations (from GenCC):

• Seckel syndrome 7

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

LOC124903313 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.207).
• BP6: Variant 14-50743529-A-G is Benign according to our data. Variant chr14-50743529-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211615.
• BP7: Synonymous conserved (PhyloP=0.528 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00691 (1053/152296) while in subpopulation AFR AF = 0.0246 (1021/41556). AF 95% confidence interval is 0.0233. There are 22 homozygotes in GnomAd4. There are 486 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020921.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIN	NM_020921.4	MANE Select	c.5188T>C	p.Leu1730Leu	splice_region synonymous	Exon 24 of 31	NP_065972.4
	NIN	NM_182946.2		c.5188T>C	p.Leu1730Leu	splice_region synonymous	Exon 24 of 30	NP_891991.2	Q8N4C6-1
	NIN	NM_182944.3		c.5188T>C	p.Leu1730Leu	splice_region synonymous	Exon 24 of 30	NP_891989.3	C9J066

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIN	ENST00000530997.7	TSL:5 MANE Select	c.5188T>C	p.Leu1730Leu	splice_region synonymous	Exon 24 of 31	ENSP00000436092.2	Q8N4C6-7
	NIN	ENST00000382041.7	TSL:1	c.5188T>C	p.Leu1730Leu	splice_region synonymous	Exon 24 of 30	ENSP00000371472.3	Q8N4C6-1
	NIN	ENST00000382043.8	TSL:1	c.3049T>C	p.Leu1017Leu	splice_region synonymous	Exon 22 of 28	ENSP00000371474.4	Q8N4C6-11

Frequencies

GnomAD3 genomes AF: 0.00691 AC: 1052 AN: 152178 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00166 AC: 416 AN: 251290 AF XY: 0.00122

Gnomad AFR exome AF: 0.0242

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000672 AC: 977 AN: 1454388 Hom.: 14 Cov.: 27 AF XY: 0.000592 AC XY: 429 AN XY: 724052

African (AFR) AF: 0.0255 AC: 850 AN: 33336

American (AMR) AF: 0.000582 AC: 26 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5740

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105378

Other (OTH) AF: 0.00141 AC: 85 AN: 60138

GnomAD4 genome AF: 0.00691 AC: 1053 AN: 152296 Hom.: 22 Cov.: 32 AF XY: 0.00653 AC XY: 486 AN XY: 74466

African (AFR) AF: 0.0246 AC: 1021 AN: 41556

American (AMR) AF: 0.00157 AC: 24 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00249 Hom.: 9

Bravo AF: 0.00780

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	NIN-related disorder (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.1
DANN	Benign	0.74
PhyloP100		0.53
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61741547; hg19: chr14-51210247;